PROJECT SUMMARY The overall goal of this effort is to organize the first and largest international multicenter, multi-racial and ethnic consortium of retinoblastoma (RB) survivors to study health outcomes and interrogate genotype-phenotype correlations of disease presentation. Intraocular RB is virtually 100% curable in high-income countries and treatment thus focuses on globe salvage with preservation of functional vision and minimizing acute and long- term adverse outcomes. RB has been curable for decades with enucleation or radiation therapy. However, the morbidity of eye removal, visual impairment, orbital and facial deformities, psychosocial and neurocognitive impairment and high subsequent malignant neoplasm (SMN) rates prompted in the 1990's the use of intravenous chemotherapy with local ophthalmic therapies (IVC). Failure of globe salvage in up to 40% of eyes with IVC, combined with systemic toxicities led to the increased use of intra-arterial chemotherapy (IAC) since 2008. IVC and IAC are believed to be associated with excellent patient centered outcomes and lower SMN rates than enucleation or radiation. IVC is potentially associated with more systemic toxicities, while IAC with greater local toxicity. Therapeutic options are thus, in part, determined by acute and long-term toxicities. Treatment must also be determined by likelihood of cure with globe and vision savage, which is heavily influenced by disease presentation, and in particular, vitreous and subretinal seeds. However, the biologic basis of seed development remains largely unknown. Such knowledge can inform choice of therapy and lead to development of targeted therapies associated with an improved balance of efficacy and toxicity. No organized systematic approach has been undertaken to assess acute toxicities and long-term outcomes of IVC and IAC or the biologic determinants of aggressive disease presentation, which drives therapeutic decisions, and in turn, health outcomes. We have therefore assembled pediatric oncology and ophthalmology investigators to form the Research Into Visual Endpoints and RB Health Outcomes After Treatment (RIVERBOAT) Consortium to: 1) define acute toxicity and visual outcomes in RB survivors and compare patient-centered psychosocial and neurocognitive outcomes in survivors with normative data and sibling controls; 2) create the first Clinically-Annotated Patient Tissues to Analyze gene INteractions to assess biologic correlates of disease and to facilitate future research: RIVERBOAT- CAPTAIN Biorepository; and 3) using the RIVERBOAT-CAPTAIN biorepository, determine the interplay between specific RB1 mutation type and the role of additional modifier genes in determining tumor phenotypes that drive treatment decisions. We will positively impact survivors of RB by: 1) assessing short and long-term outcomes of contemporary therapy; 2) establishing a clinically-annotated biorepository for genomic research; and 3) examining molecular pathogenesis of disease presentation. This will address the goal of RB management: globe and vision preservation without treatment-related adverse sequelae.